1-phenyl-4-amino-cyclohex-2-ene-1-carboxylic acid ethyl esters

ABSTRACT

The invention relates to 1-phenyl-4-amino-cyclohex-2-ene-1-carboxylic-acid-esters of the general formula I ##SPC1## 
     wherein R 1  and R 2  may be the same or different and may be H, alkyl, hydroxyalkyl, alkenyl, preferably with 1 to 4 C-atoms, aralkyl which may be bonded to each other, in which connection the heterocyclic system formed may be substituted further by the OH-- group and where attachment takes place by an oxygen or a nitrogen atom, if desired, which in its turn carries an H, alkyl with 1 to 4 C-atoms, aryl which may be substituted by chlorine, preferably in 3 or 4-position, and by methoxy, preferably in 2 or 4-position, acyl, preferably alkanoyl with 1 to 4 C-atoms, and aroyl, or aralkyl, and R 3  represents an alkyl radical with 1 to 4 C-atoms, the salts thereof and quarternary ammonium compounds, and a process for their preparation. These compounds have analgesic and neuroleptic properties.

It has been surprisingly found that cyclohexenes of the general formulaII: ##SPC2##

wherein Y means a nucleophilically exchangeable group such as Cl--,Br--, J--, CH₃ SO₂ --O--, p--CH₃ --C₆ H₄ --SO₂ --O--, C₆ H₅ SO₂ --O--,p--Br-- --C₆ H₄ SO₂ --O--, p--NO₂ --C₆ H₄ --SO₂ --O--, p--NO₂ --C₆ H₄--CO--O-- etc. react with amines of the general formula H--NR₁ --R₂ in asmooth reaction to form1-phenyl-4-amino-cyclohex-2-ene-1-carboxylic-acid-esters of the generalformula I ##SPC3##

wherein R₁ and R₂ may be the same or different and may be H, alkyl,hydroxyalkyl, alkenyl, preferably with 1 to 4 C-atoms, aralkyl which maybe bonded to each other, in which connection the heterocyclic systemformed may be substituted further by the OH- group and where attachmenttakes place by an oxygen or a nitrogen atom, if desired, which in itsturn carries an H, alkyl with 1 to 4 C-atoms, aryl which may besubstituted by chlorine, preferably in 3 or 4-position, and by methoxy,preferably in 2 or 4-position, acyl, preferably alkanoyl with 1 to 4C-atoms, and aroyl, or aralkyl, and R₃ represents an alkyl radical with1 to 4 C-atoms.

In general the reaction is performed by allowing the amines HNR₁ R₂ toreact with the compounds II in an organic solvent, preferably indioxane, dimethylformamide, dimethylsulfoxide, ethanol or acetonitrile,occasionally, however, also in the absence of a solvent in the presenceor in the absence of an auxiliary base, at temperatures between 10° and160°C.

According to the invention it is possible, furthermore, to transform acompound of the general formula I into the acid addition salt accordingto previously known methods, e.g. by treatment with a physiologicallyacceptable inorganic or organic acid such as hydrochloric acid,phosphoric acid, sulphuric acid or tartaric acid, fumaric acid, ascorbicacid, oxalic acid etc. It is possible, too, to quarternize a compound ofthe general formula I at the nitrogen, according to the usual methods,e.g. by treatment with an alkyl halide.

According to the invention the compounds of the general formula II canbe prepared by various methods.

a. A cyclohexene derivative of the general formula III ##SPC4##

(r₃ has the above meaning) can be reacted with acid halides, such asPCl₅, POCl₃, PBr₃, POBr₃, SOCl₂, CH₃ COBr etc. or with hydro halogenicacids, in a fundamentally known manner. Preferably this reaction isperformed in an inert solvent, such as benzene, chloroform or carbontetrachloride; reaction with hydro halogenic acids, however, may also besuccessfully effected in the aqueous or alcoholic phase or in glacialacetic acid.

b. A cyclohexene derivative of the general formula III can be reactedwith a sulphonic acid chloride, such as methanesulphonic acid chloride,p-toluenesulphonic acid chloride, p-nitrobenzenesulphonic acid chlorideetc., in a fundamentally known manner in the presence of a base,preferably in the presence of pyridine, using a solvent or not.

c. The 1-phenyl-2-acetoxy-cyclohex-3-ene-1-carboxylic-acid-esters of thegeneral formula IV, preparation of which according to the invention isdescribed below, can be converted directly into compounds of the generalformula II (for Y = halogen) by treatment with aqueous-hydro halogenicacids or with thionyl halides.

d. The 1-phenyl-2-dialkylamino-cyclohex-3-ene-1-carboxylic-acid esterscan be converted directly into the compounds of the general formula II(for Y = J) by reaction with at least 2 equivalents of alkyliodide in aninert solvent, at temperatures between 15° and 80°C; this reaction willbe illustrated by the following example: ##SPC5##

The 1-phenyl-2-acetoxy-cyclohex-3-ene-1-carboxylic-acid-esters of thegeneral formula IV ##SPC6##

used as the starting material, are prepared according to the inventionby a one-container-reaction of the components crotonaldehyde,acetanhydride and ethyl atropate, in the presence of anhydrous sodiumacetate. In detail, the process is as follows: The ethyl atropate andthe crotonaldehyde are introduced into a suspension of sodium acetate inacetanhydride acting at the same time as a solvent in this connection,and the mixture is heated to boiling for 3 - 8 h., preferably 6 h.

The compounds obtained according to the invention exhibit outstandinganalgesic and neuroleptic properties, the presence of both propertiestogether in one substance representing a surprising and novel fact.Those compounds of the general formula I wherein R₁ and R₂ are eitherdirectly or by a nitrogen atom connected to form a ring have proved tobe especially effective in this connection. In addition, a markedspasmolytic activity -- mostly combined with analgesic and/or sedativecomponents -- is found in numerous representatives of the productsaccording to the invention.

The new substances can be processed into any type of preparation in usefor pharmaceutical purposes; thus e.g. coated tablets, tablets,emulsions, solutions for injection etc. can be prepared from them.

EXAMPLE 11-Phenyl-4-dimethylamino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .hydrochloride

Method A

1-Phenyl-2-acetoxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester

1 mole (170 g) of ethyl atropate, 210 g of crotonaldehyde, 150 g ofanhydrous sodium acetate and 0.6 l of acetanhydride are heated toboiling for 6 h. while stirring. Subsequently the main amount of theliquid phase is distilled off under vacuum, and the residue is extractedwith 1 liter of hot ligroin. The residue of the ligroin phase isdistilled. The product -- although being pure according to gaschromatography -- distills in a wide boiling range: b.p.₀,₁ 130°-165°C.Yield: 105 g. It crystallizes when allowed to stand. M.P. 72°-73°C (frompetroleum ether).

C₁₇ H₂₀ O₄ (288.4)

Calc.: C, 70.79; H, 6.99; O, 22.19. Found: C, 70.95; H, 7.15; O, 21.79.

1-Phenyl-2-hydroxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester

75 g of the above product are heated under reflux for 10 hrs. in amixture of 200 cc. of ethanol and 150 cc. of 2N NaOH. Most of theethanol is removed in vacuum, the residue poured into water, and theaqueous phase extracted with ethyl acetate. Following drying, thesolvent is removed, and the residue distilled. b.p.₀,₁ 118°-120°C.Yield: 60 g.

C₁₅ H₁₈ O₃ (246.3)

Calc.: C, 73.14; H, 7.37; O, 19.48. Found: C, 72.56; H, 7.43; O, 20.10.

1-Phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester

A solution of 60 g of the above cyclohexenol in 120 cc. of benzene isadded drop by drop at a temperature below 50°C to a solution of 60 g ofPCl₅ in 300 cc. of benzene. After stirring for 2 days at 20°C andsubsequent washing with a large amount of water and a small amount ofdilute sodium hydroxide solution, the benzene phase is dried over CaCl₂.The residue of the benzene phase is distilled. b.p.₀,₀₁ 119°-121°C.Yield: 41 g.

C₁₅ H₁₇ ClO₂ (264.8)

Calc.: C, 68.04; H, 6.47; Cl, 13.40. Found: C, 67.54; H, 6.32; Cl,13.00.

26 g (0.1 mole) of the above chlorocyclohexene are introduced into 150cc. of a 10 % solution of dimethylamine in dimethylformamide. Theproduct is allowed to stand over night, and the following day, during 7hrs., a moderate stream of dimethylamine is conducted through thesolution heated to 90°C. Then reduction in vacuum is effected, theresidue taken up in 2 N HCl and freed of neutral substances withbenzene. The aqueous phase is alkalized, and the separated oil taken upin ether. The hydrochloride is precipitated from the dried etherealphase by means of a 10% solution of HCl gas in ethyl acetate. Yield: 30g (crude), 16 g (p.a.). m.p. 158°-9°C (with 0,25.H₂ 0: 138°-9°C) (fromdioxane-ether or ethyl acetate-isopropanol). C₁₇ H₂₄ ClNO₂ . 0,25 H₂ O(314.4)

Calc.: C, 64.94; H, 7.85; N, 4.46; Cl, 11.27. Found: C, 64.94; H, 7.59;N, 4.56; Cl, 10.91.

Method B

1-Phenyl-2-chloro-cyclohex-3-ene-carboxylic-acid-ethyl-ester

200 g of 1-phenyl-2-acetoxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare dissolved in 1 liter of 96% ethanol. The solution is charged with190 g of HCl gas and heated under reflux for 2 hrs. The solvent isremoved and the residue directly fractionated in the vacuum, b.p.₀,₁130°C. Yield: 169 g. Gaschromatographically homogeneous. Infraredspectroscopically identical with the product prepared according to A.

20 g of this compound are reacted with dimethylamine indimethylformamide according to Method A. 8 g of the hydrochloride of theabove compound are obtained as the 0,25-hydrate with an melting point of137°-9°C by process as described under A.

Method C

While shaking, 2.5 g of freshly distilled methane sulfonic acid chlorideare added drop by drop at 5°C to 5 g of1-phenyl-2-hydroxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterdissolved in 10 ml of pyridine. The batch is allowed to stand for 3 daysat 5°C, then it is poured into 100 ml of 2N HCl and extracted withbenzene. The benzene residue forms a non-distillable oil, which isthin-layer-chromatographically homogeneous and which proves infraredspectroscopically to be the mesylate of the cyclohexanol. 2 g of themesylate are taken up with 10 cc. of a 10% dimethylamine solution indimethylformamide, and kept for 24 hrs. at 20°C and for 2 hrs. at 90°C.The product is introduced into diluted HCl and, after removing theneutral substances, alkalized with 2N NaOH. The hydrochloride of theabove compound is precipitated as described, after taking up theseparated base in ethyl acetate. Yield 0.5 g of the melting point158°-9°C (anhydrous).

C₁₇ H₂₄ ClNO₂ (309.89)

Calc.: Cl, 11.45., Found: Cl, 11.46

Method D

1-Phenyl-2-iodo-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester

27.3 g (0.1 mole) of1-phenyl-2-dimethylamine-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare heated with 28.4 g (0.2 moles) of methyl iodide for 5 hrs. to 60°Cin 100 cc. of dioxane. After cooling, it is sucked off from thetetramethylammonium iodide (19.9 g). The dioxane phase is evaporated at40°C in vacuum, the residue taken up in benzene and extracted with 1NHCl. The benzene phase is washed with water and under protection fromlight is distilled off in vacuum. Residue: 35 g of dark-red,non-distillable oil.

C₁₅ H₁₇ JO₂ (356.2)

Calc.: J, 35.5. Found: J, 30.0.

35 g of the iodo-cyclohexene are taken up in 100 cc. of benzene, treatedwith a solution of 13.8 g of dimethylamine in 200 cc. of benzene andpreserved in a dark place at room temperature for 24 hrs. 19.4 g ofdimethylamine . hydro-iodide are filtered off. Then the benzene phase isextracted with 2N HCl, and the aqueous phase alkalized. 6.0 g ofhydrochloride of the melting point 160°C (anhydrous) are precipitated asdescribed under A from the dried ethereal extract.

C₁₇ H₂₄ ClNO₂ (309.89)

Calc.: Cl, 11.45. Found: Cl, 11.21.

Methoiodide

2.7 g of1-phenyl-4-dimethylamino-cyclohex-2-ene-1-carboxylic-acid-ethyl-esterare dissolved in 10 cc. of dioxane and 1.5 g of CH₃ J The solution warmsand the metho-iodide precipitates. Yield: 4 g, m.p. 191°-2°C (frommethanol).

C₁₈ H₂₆ JNO₂ (415.32)

Calc.: J, 30.56. Found: J, 30.67.

EXAMPLE 21-Phenyl-4-diethylamino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .hydrochloride

40 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare heated for 3 hrs. to 90°C in a covered glass autoclave with asolution of 45 g of diethylamine in 200 cc. of dimethylformamide. Thesolvent is distilled off in vacuum, and the residue, processed asdescribed in example 1, method A. The hydrochloride is precipitated fromethyl acetate. Yield: 10.0 g, m.p. 135°-7°C (from methyl ethyl ketone).

C₁₉ H₂₈ ClNO₂ (337.9)

Calc.: C, 67.53; H, 8.35; Cl, 10.49; N, 4.14. Found: C, 67.48; H, 8.14;Cl, 10.21; N, 4.31.

EXAMPLE 31-Phenyl-4-N-morpholino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .hydrochloride

Method A

44 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare dissolved in 250 cc. of dimethylformamide and incubated for 3 hrs.at 90°C with 45 g of morpholine. The product is then poured into 2N HCl,freed of neutral substances by extracting with toluene and then againset free by alkalizing with 2N NaOH. It is taken up in ether andprecipitated as hydrochloride by means of HCl gas. The hydrochloride isdigested with diisopropyl ether and then recrystallized from ethylmethyl ketone. Yield: 9.5 g, m.p. 173°-6°C.

C₁₉ H₂₆ ClNO₃ (351.86)

Calc.: C, 64.85; H, 7.45; Cl, 10.08; N, 3.98. Found: C, 64.80; H, 7.42;Cl, 9.84; N, 3.92.

Method B

1-Phenyl-2-bromo-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester

14.2 g of1-phenyl-2-hydroxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester areheated to boiling for 30 minutes with 40 cc. of acetyl bromide. Then theproduct is taken up in toluene and washed until free of acid. Theresidue of the dried toluene phase is distilled in vacuo. b.p.₀,₅ 142°C.Yield: 16,4 g, n_(D) ²⁰ 1.5592.

6.2 of this compound are heated for 2 hrs. to 100°C with 6.0 g ofmorpholine in 25 cc. of DMSO. After cooling the product is introducedinto water, and the separated base taken up in ether. Followingextraction with water, the organic phase is dried, and the hydrochlorideof the above compound precipitated by introducing HCl gas. Yield: 5.0 g,m.p. 176°C.

C₁₉ H₂₆ ClNO₃ (351.86)

Calc.: C, 64.85; H, 7.45; Cl, 10.08; N, 3.98. Found: C, 64.76; H, 7.45;Cl, 10.26; N, 3.97.

EXAMPLE 41-Phenyl-4-(2-phenylethylamino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

Method A

40 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterand 36 g of β-phenylethylamine in 250 cc. of dimethylformamide areheated for 3 hrs. to 90°C. The solvent is removed under vacuum in therotary evaporator, and the residue introduced into water. Extraction iseffected with toluene, and the toluene phase saturated with aqueous 2NHCl. On standing, the hydrochloride, which is sparingly soluble inwater, separates. Recrystallization from benzene is effected. Yield:16.9 g, m.p. 179°-82°C.

C₂₃ H₂₈ ClNO₂ (385.92)

Calc.: C, 71.58; H, 7.31; N, 3.63; Cl, 9.19. Found: C, 71.66; H, 7.11;N, 3.87; Cl, 9.87.

Method B

15 g of 1-phenyl-2-hydroxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterand 15 cc. of thionyl chloride and 1 cc. of dimethylformamide are heatedunder reflux for 10 minutes. Then direct distillation is done. 12.2 g of1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester of theboiling point 0.1/122°-5°C are obtained. By reacting with 12 g ofβ-phenylethyl amine in 100 cc. of DMSO for 2 hrs. at 100°C, processingas described above, 6.0 g of hydrochloride m.p. 179°-82°C are obtained.

EXAMPLE 5 1-Phenyl-4-(N₄ -phenyl-N₁-piperazino(-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .hydrochloride

Method A

50 g of N-phenyl-piperazine and 35 g of1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester aredissolved in 250 cc. of dimethylformamide and heated for 3 hrs. to 90°C.The solvent is distilled off, and the residue digested with 1.5 l ofwater. The pH-value is adjusted to 5 by means of diluted HCl, theundissolved material filtered off and taken up in chloroform. This phaseis washed with water, dried and concentrated. The residue is taken up inbenzene and precipitated as hydrochloride by introducing HCL gas. Yield:12.2 g (from benzene), m.p. 193°-5°C.

C₂₅ H₃₁ ClN₂ O₂ (426.97)

Calc.: C, 70.33; H, 7.32; Cl, 8.30; N, 6.56. Found: C, 70.37; H, 7.35;Cl, 8.13; N, 6.37.

Method B

Following addition of 5 g of N-phenyl-piperazine, a solution of 4.0 g of1-phenyl-2-bromo-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester in 20 cc.of DMSO is kept at 100°C for 2 hrs. After adding 100 cc. of toluene,extraction with water is effected several times and then the toluenephase dried over CaCl₂. The residue from this phase is taken up in etherand precipitated by dropwise adding ethereal hydrochloric acid. Yieldfollowing recrystallization from benzene: 4.0 g, m.p. 198°-200°C.

C₂₅ H₃₁ ClN₂ 0₂ (426.97)

Calc.: C, 70.33; H, 7.32; Cl, 8.30; N, 6.56. Found: C, 70.32; H, 7.37;Cl, 8.48; N, 6.27.

Method C

35 g of 1-phenyl-2-iodo-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester aredissolved in 200 cc. of dioxane, and 32 g of phenyl-piperazine are addedto the solution. After 2 hrs., filtration from thephenyl-piperazine-hydro-iodide (30 g) is effected, and the crude base(33.8 g) is obtained by distilling off the dioxane. After this mildpreparation, the base is so pure that it crystallizes: m.p. 95°-96°C(from hexane). 21.6 g of hydrochloride with m.p. 200°C may be preparedfrom it.

EXAMPLE 61-Phenyl-4-benzylamino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .oxalate

40 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare dissolved in 400 cc. of dry acetonitrile and, following addition of48 g of benzylamine, heated to boiling for 2 hrs. The solvent isdistilled off, and the residue taken up in 2N HCl. The neutral productsare extracted with ether. The aqueous phase is alkalized and theseparated oil precipitated from ethyl acetate with oxalic acid. Yield:11.8 g, m.p. 207°C (from methanol).

C₂₄ H₂₇ O₆ N (425.46)

Calc.: C, 67.74; H, 6.40; N, 3.30. Found: C, 67.38; H, 6.37; N, 3.66.

EXAMPLE 71-Phenyl-4-methylamino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .hydrochloride

40 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare dissolved in 250 cc. of monomethylformamide and saturated withmethylamine at 2 atmospheres. The product is warmed for 4 hrs. to 70°Cin a glass autoclave, then poured into 1.5 l of water and acidified with2N HCl. The ether extract is discarded and the aqueous phaseprecipitated as hydrochloride with HCl-gas in ether. Yield: 19.2 g (fromisopropanol), m.p. 162°-3°C.

C₁₆ H₂₂ ClNO₂ (395.8)

Calc.: C, 64.96; H, 7.50; Cl, 11.99; N, 4.73. Found: C, 65.04; H, 7.49;Cl, 11.71; N, 5.04.

Example 8 1-Phenyl-4-amino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. naphthalene-1,5-disulfonate

45 g of 1-phenyl-2-hydroxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare introduced into 320 cc. of absolute ethanol charged with 8% gaseousHCl. The product is allowed to stand for 24 hrs. at 20°C, then thesolvent and the excess HCl are removed in vacuo, and the residue takenup in 400 cc. of fresh ethanol. Following addition of 1 g of NH₄ Cl, NH₃is pressed on for 5 hrs. at 80°C under 5 atmospheres. It is distilled todryness, and the residue taken up in 2N HCl. It is freed of the neutralpart in the usual manner and alkalized. The base is taken up in ether;removal of the solvent is effected, and the residue precipitated inisopropanol as naphthalene-1,5-disulfonate. Yield: 11 g, m.p. 325°C(from ethanol).

C₄₀ H₄₆ N₂ O₁₀ S₂ (778.92)

Calc.: C, 61.68; H, 5.95; N, 3.58; S, 8.23. Found: C, 61.60; H, 6.11; N,3.80; S, 8.18.

EXAMPLE 91-Phenyl-4-(N-metnyl-N-allyl-amino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

30 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-estertogether with 19.5 g of N-methyl-N-allylamine are heated for 1 hr. to90°C in a mixture of 300 cc. of dimethylformamide and 60 cc. of toluene.Processing is effected as described in example 7. Yield: 8.8 g ofhydrochloride, m.p. 153°-5°C (from isopropanol-ethyl acetate).

C₁₉ H₂₆ ClNO₂ (335.88)

Calc.: C, 67.73; H, 7.65; Cl, 10.59; N, 3.83. Found: C, 67.93; H, 7.80;Cl, 10.56; N, 3.17.

EXAMPLE 10 1-Phenyl-4-(N₄-methyl-piperazino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .dihydrochloride

26.5 g of1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester, 11 g ofN-methyl-piperazine and 22 g of ethyl-diisopropylamine are heated for 10minutes on the oil bath to 126°C. After cooling, the product is taken upin ether, sucked off, the ether phase is dried, and the residue taken upin chloroform. Extraction is effected with water, the dried CHCl₃ phaseconcentrated. The residue is taken up in ether and the hydrochloride isprecipitated with HCl gas. Yield: 12.0 g, m.p. 233°-5°C (fromisopropanol).

C₂₀ H₃₀ Cl₂ N₂ O₂ (401.36)

Calc.: C, 59.85; H, 7.53; Cl, 17.66; N, 6.98. Found: C, 59.59; H, 7.41;Cl, 17.30; N, 6.81.

EXAMPLE 11 1-Phenyl-4-(N₄-2-phenylethyl-piperazino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. dihydrochloride

26.5 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare heated for 2 hrs. to 150°C with 0.1 mole of β-phenylethyl-piperazineand 22 g of ethyl-diisopropylamine. After cooling, the product is takenup in ether; the ether phase is filtered and evaporated. The residue istaken up in fresh ether and saturated with 1N HCl. The dihydrochloride,which is sparingly soluble in water and ether, separates. It isrecrystallized from isopropanol. Yield: 13.0 g, m.p. 272°-3°C.

C₂₇ H₃₆ Cl₂ N₂ O₂ (491.51)

Calc.: C, 65.97; H, 7.39; Cl, 14.42; N, 5.70. Found: C, 65.94; H, 7.50;Cl, 14.27; N, 5.69.

EXAMPLE 12 1-Phenyl-4-(N₄-benzyl-piperazino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .dihydrochloride

26.5 g of1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester, 17.7 gof N-benzyl-piperazine and 22 g of ethyl-diisopropylamine are heatedfirst for 30 minutes to 100°C and then for 15 minutes to 150°C.Processing is effected as described in example 11; afterrecrystallization from isopropanol, 15.2 g, m.p. 251°-3°C are obtained.

C₂₆ H₃₄ Cl₂ N₂ O₂ (477.46)

Calc.: C, 65.40; H, 7.18; Cl, 14.86; N, 5.87. Found: C, 65.20; H, 6.97;Cl, 14.44; N, 5.61.

EXAMPLE 13 1-Phenyl-4-(N₄-4'-methoxyphenyl-piperazino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

20 g of 1-(p-methoxy-phenyl)-piperazine are dissolved in 200 cc. ofDMSO, mixed with 25 g of1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester and 20 gof N-ethyl-diisopropylamine and heated for 3 hrs. to 100°C. Afterdistilling off the solvent, the residue is digested with 0.5N HCl andafter decanting taken up in ether. On standing, the hydrochlorideseparates. It is recrystallized from benzene. Yield: 3.0 g, m.p.190°-1°C.

C₂₆ H₃₃ ClN₂ O₃ (457.03)

Calc.: C, 68.33; H, 7.28; Cl, 7.76; N, 613. Found: C, 68.17; H, 7.07;Cl, 7.93; N, 6.07.

EXAMPLE 14 1-Phenyl-4-(N₄-2'-methoxyphenyl-piperazino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

Preparation as described in example 13. Yield: 8.3 g, m.p. 182°-3°C(from benzene).

C₂₆ H₃₃ ClN₂ O₃ (457.03)

Calc.: C, 68.33; H, 7.28; Cl, 7.76; N, 6.13. Found: C, 68.21; H, 7.40;Cl, 7.80; N, 6.28.

EXAMPLE 15 1-Phenyl-4-(N₄-4'-chlorophenyl-piperazino)-cyclohex-2-ene-1-carboxylix-acid-ethyl-ester. hydrochloride

Preparation as described in example 13 (20 g of N₁-(4-chloro-phenyl)-piperazine). Yield: 14.0 g, m.p. 198°-200°C (frombenzene or isopropanol).

C₂₅ H₃₀ Cl₂ N₂ O₂ (461.45)

Calc.: C, 65.07; H, 6.56; Cl, 15.37; N, 6.07. Found: C, 65.14; H, 6.73;Cl, 15.22; N, 5.75.

EXAMPLE 161-Phenyl-4-(4'-benzyl-piperidino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

30 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare heated together with 45 g of benzylpiperidine in 150 cc. of DMSO for21/2 hrs. to 100°C. The product is poured into 1.5 l of ice water,acidified with 1N HCl and extracted with ether. An oil, whichcrystallizes on digestion with water, separates from the ether phase.Recrystallization is effected first from toluene, then from ethylacetate. Yield: 19.0 g, m.p. 142°C (as semihydrate).

C₂₇ H₃₅ ClNO₂,₅ (449.05)

Calc.: C, 72.21; H, 7.86; Cl, 7.90; N, 3.12. Found: C, 72.16; H, 7.83;Cl, 7.80; N, 3.01.

EXAMPLE 171-Phenyl-4-N-piperidino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .hydrochloride

Method A

57.6 g of1-phenyl-2-acetoxy-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester and 160cc. of thionyl-chloride and 3.6 cc. of water are heated under reflux for30 minutes. The whole is distilled off in the rotary evaporator to100°C/20 Torr, the residue is taken up in 100 cc. of DMSO, and 30 g ofpiperidine are added. The batch is heated for 3 hrs. to 100°C, thenpoured into ice water and adjusted to pH 3 by means of 2N HCl. Neutralproducts are removed with toluene. The aqueous phase is alkalized withammonia and the separated oil taken up in ether. The hydrochloride isprecipitated from the dried ether phase by means of HCl gas. Yield: 20.2g, m.p. 216°-7°C (from isopropanol).

C₂₀ H₂₈ ClNO₂ (349.91)

Calc.: C, 68.65; H, 8.06; Cl, 10.13; N, 4.00. Found: C, 68.95; H, 8.19;Cl, 10.09; N, 4.30.

Method B

35 g of 1-phenyl-2-iodo-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester aretaken up in 200 cc. of dioxane, 17 g of piperidine are added andpreserved for 12 hrs. at room temperature in a dark place. Then most ofthe solvent is distilled off, and the residue introduced into 300 cc. ofwater. Extraction is effected with ether, and the hydrochlorideprecipitated from the washed and dried phase by means of HCl gas. Yield:29.0 g, m.p. 215°-17°C (from isopropanol).

EXAMPLE 18

1-Phenyl-4-(N₄-3'-chlorophenyl-piperazino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester.hydrochloride

Preparation is effected as described in example 15. Yield: 10.5 g, m.p.188°-90°C (from isopropanol).

C₂₅ H₃₀ Cl₂ N₂ O₂ (461.45)

Calc.: C, 65.07; H, 6.56; Cl, 15.37; N, 6.07. Found: C, 64.88; H, 6.49;Cl, 15.28; N, 5.85.

EXAMPLE 191-Phenyl-4-(4'-phenyl-piperidino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

32 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare dissolved in 100 cc. of dioxane, 16 g of 4-phenyl-piperidine and 30g of ethyl-diisopropylamine are added and heated for 3 hrs. to 100°C.Processing is effected as described in example 13. Yield: 12 g, m.p.238°-40°C (from toluene).

C₂₆ H₃₂ ClNO₂ (426.01)

Calc.: C, 73.30; H, 7.57; Cl, 8.32; N, 3.29. Found: C, 73.09; H, 7.65;Cl, 8.35; N, 3.46.

EXAMPLE 20 1-Phenyl-4-(N₄-benzoyl-piperazino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester .hydrochloride

35 g of N-benzoyl-piperazine and 40 g of1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester and 35 gof ethyl-diiospropylamine in 100 cc. of DMSO are heated for 21/2 hrs. to100°C. Processing is effected as described in example 13. Yield: 12.5 g,m.p. 185°-7°C (from isopropanol).

C₂₆ H₃₄ ClN₂ O₃

Calc.: C, 68.63; H, 6.87; Cl, 7.79; N, 6.16. Found: C, 68.69; H, 7.02;Cl, 7.84; N, 6.14.

EXAMPLE 211-Phenyl-4-(4'-methyl-piperidino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

25 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester,30 g of 4-methyl-piperidine and 100 cc. of DMSO are heated for 3 hrs. to100°C. Most of the solvent is distilled off in vacuo, and the residueacidified with 2N HCl, the hydrochloride is separating. It isrecrystallized from isopropanol. Yield: 23.3 g, m.p. 220°-22°C.

C₂₁ H₃₀ ClNO₂ (363.94)

Calc.: C, 69.30; H, 8.31; Cl, 9.74; N, 3.85. Found: C, 69.15; H, 8.38;Cl, 9.66; N, 3.73.

EXAMPLE 221-Phenyl-4-(4'-hydroxy-piperidino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. oxalate

20 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare heated for 3 hrs. to 100°C with 20 g of 4-hydroxypiperidine and 100cc. of DMSO. Then the product is diluted with toluene and extracted withwater and then with 2N HCl, and the hydrochloric phase alkalized with 2NNaOH. The separated phase is taken up in ethyl acetate and precipitatedwith oxalic acid. Yield: 5.3 g (from acetonitrile-ethyl acetate), m.p.166°-8°C.

C₄₂ H₅₆ N₂ O₁₀ (748.92)

Calc.: C, 67.36; H, 7.54; N, 3.75. Found: C, 67.08; H, 7.38; N, 3.54.

EXAMPLE 231-Phenyl-4-(N-methyl-N-β-phenethyl-amino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

22 g of 1-phenyl-2-chloro-cyclohex-3-ene-1-carboxylic-acid-ethyl-esterare dissolved in 100 cc. of DMSO and heated for 3 hrs. to 110°C togetherwith 22 g of N-methyl-N-β-phenethylamine. The product is acidified withdiluted HCl and extracted with toluene. On cooling to 5°C, thehydrochloride separates. It is digested with cold CHCl₃ andrecrystallized from toluene. Yield: 14.2 g, m.p. 148°-150°C.

C₂₄ H₃₀ ClNO₂ (399.97)

Calc.: C, 72.07; H, 7.56; Cl, 8.86; N, 3.50. Found: C, 72.21; H, 7.61;Cl, 8.92; N, 3.42.

EXAMPLE 241-Phenyl-4-(di-n-butylamino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. hydrochloride

35 g of 1-phenyl-2-iodo-cyclohex-3-ene-1-carboxylic-acid-ethyl-ester aredissolved in 250 cc. of dioxane, mixed with 26 g of di-n-butylamine andpreserved for 20 hrs. at room temperature in a dark place. Then theproduct is introduced into sufficient 2N HCl, extracted with ether, andthe aqueous phase alkalized with ammonia. The separated oil is taken upin ethyl acetate and washed with water several times. By the addition ofa solution of HCl gas in ethyl acetate, the hydrochloride is separated;it is recrystallized from isopropanol by adding ethyl acetate. Yield:11.3 g, m.p. 123°-4°C

C₂₃ H₃₅ ClNO₂ (392.97)

Calc.: C, 70.29; H, 8.98; Cl, 9.02; N, 3.56. Found: C, 70.11; H, 8.99;Cl, 9.20; N, 3.47.

According to the same method, there can also be prepared

25.1-[N-methyl-N-(α-methyl-β-hydroxyphenethyl)-amino]-4-phenyl-4-ethoxycarbonyl-cyclohexene-(2).sup.. HCl

C₂₅ H₃₂ ClNO₄ (430.0) M.p. 231°-4° (from ethanol)

Calc. Cl, 8.25. Found Cl, 8.27.

R₁ = CH₃ ##EQU1##

26. 1-N-piperidino-4-phenyl-4-ethoxycarbonyl-cyclohexene-(2) .sup..methiodide

C₂₁ H₃₀ INO₂ (455.4)

Calc. I, 27.87. Found I, 27.66.

M.p. 185°-6° (from isopropanol)

27.1-N-methyl-N-γ-phenylpropylamino-4-phenyl-4-ethoxycarbonyl-cyclohexene-(2).sup.. HCl

C₂₅ H₃₂ ClNO₂ (414.0)

Calc. Cl, 8.56. Found Cl, 8.87.

M.p. 149°-52° (from toluene)

R₁ = CH₃

R₂ = C₆ H₅ (CH₂)₃ -- and

28.1-N-methyl-N-β-phenylisopropylamino-4-phenyl-4-ethoxycarbonyl-cyclohexene-(2).sup..HCl

C₂₅ H₃₂ ClNO₂ (414.0)

Calc. Cl, 8.56. Found Cl, 8.56.

M.p. 148°-1° (from toluene).

We claim: 1.1-Phenyl-4-dimethylamino-cyclohex-2-ene-1-carboxylic-acid-ethylester. 2.1-Phenyl-4-diethylamino-cyclohex-2-ene-1-carboxylic-acid-ethylester. 3.1-Phenyl-4-(2-phenylethylamino)-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester.4. 1-Phenyl-4-benzylamino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester.5. 1-Phenyl-4-methylamino-cyclohex-2-ene-1-carboxylic-acid-ethylester.6. 1-Phenyl-4-amino-cyclohex-2-ene-1-carboxylic-acid-ethyl-ester. 7.1-Phenyl-4(methylallyl-amino)-cyclohex-2-ene-1-carboxylic-acid-ethylester.8.1-Phenyl-4-(methyl-2-phenylethyl-amino)-cyclohex-2-ene-1-carboxylic-acid-ethylester.9.1-Phenyl-4-(di-n-butylamino)-cyclohex-2-ene-1-carboxylic-acid-ethylester.